Unveiling the role of lysosomes in antigen processing and presentation.
Lysosomes drive antigen proteolysis and peptide loading for major histocompatibility complex class II (MHCII) presentation in antigen-presenting cells (APCs), enabling activation of peptide-specific CD4+ T helper cells (CD4+ Th cells). Tight regulation of endocytic trafficking, protease activity, and peptide editing is required to generate stable peptide-MHCII complexes and balanced immune responses. Conversely, dysregulation of antigen catabolism or loading can promote impaired pathological immunity, including autoimmunity. However, key mechanistic questions remain, including how proteolysis, redox regulation, and peptide editing shape the MHCII ligandome across APC subsets and inflammatory states. In this review, we explore the main mechanisms of antigen acquisition, endocytic/lysosomal factors controlling MHCII-restricted processing and presentation, and evidence linking lysosomal dysfunction to autoimmunity. Understanding the functions of lysosomes in immune cells is crucial for elucidating their roles in physiological and pathological states, for developing targeted therapeutic strategies and for enhancing the safety and efficacy of novel biological entities (NBEs).